Citations

Abstract Combinations of bortezomib (V) and dexamethasone (D) with either lenalidomide (R) or cyclophosphamide (C) have shown significant efficacy. This randomized phase 2 trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum 8 cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms) ≥ very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances. All regimens were highly active and well tolerated in previously untreated MM, and, based on this trial, VDR and VCD-mod are preferred for clinical practice and further comparative testing. No substantial advantage was noted with VDCR over the 3-drug combinations. This trial is registered at www.clinicaltrials.gov (NCT00507442).

Abstract Although therapeutic vaccination often induces markers of tumor-specific immunity, therapeutic responses remain rare. An improved understanding of patient-specific dynamic interactions of immunity and tumor progression, combined with personalized application of immune therapeutics would increase the efficacy of immunotherapy. Here, we developed a method to predict and enhance the individual response to immunotherapy by using personalized mathematical models, constructed in the early phase of treatment. Our approach includes an iterative real-time in-treatment evaluation of patient-specific parameters from the accruing clinical data, construction of personalized models and their validation, model-based simulation of subsequent response to ongoing therapy, and suggestion of potentially more effective patient-specific modified treatment. Using a mathematical model of prostate cancer immunotherapy, we applied our model to data obtained in a clinical investigation of an allogeneic whole-cell therapeutic prostate cancer vaccine. Personalized models for the patients who responded to treatment were derived and validated by data collected before treatment and during its early phase. Simulations, based on personalized models, suggested that an increase in vaccine dose and administration frequency would stabilize the disease in most patients. Together, our findings suggest that application of our method could facilitate development of a new paradigm for studies of in-treatment personalization of the immune agent administration regimens (P-trials), with treatment modifications restricted to an approved range, resulting in more efficacious immunotherapies. Cancer Res; 72(9); 2218–27. ©2012 AACR.